There is an urgent need for new HIV-1 therapies targeting different steps of the viral replicative cycle to combat the growing prevalence of multidrug-resistant viruses and to reduce treatment toxicities. The chemokine receptor CCR5 serves as a critical portal of HIV-1 entry by acting as a fusion coreceptor in conjunction with CD4, the primary receptor for HIV-1. CCR5 plays a central role in virus transmission and pathogenesis, and therefore represents an attractive target for new HIV-1 therapies. PRO 140 is a unique humanized CCR5 monoclonal antibody (mAb) that offers a novel therapeutic profile. Unlike small-molecule CCR5 antagonists under development, PRO 140 broadly and potently inhibits CCRS-mediated HIV-1 entry without blocking or otherwise dysregulating the natural activities of CCR5. In addition, PRO 140 has demonstrated favorable tolerability and pharmacokinetic profiles in an ongoing Phase la clinical trial in healthy volunteers. PRO 140 is clearly differentiated from small molecules in terms of its lack of CCR5 antagonism, nonoverlapping patterns of viral resistance, antiviral synergy, excellent tolerability profile, and potential for infrequent (e.g., monthly) dosing. PRO 140 may therefore define a unique CCR5 inhibitor subclass. The highly innovative nature of this therapeutic approach is further underscored by the fact that no CCR5 inhibitor and no mAb to any target have been approved for HIV-1 therapy. Project 2 proposes the first use of PRO 140 in HIV-infected individuals. Our clinical research also represents the first use of a CCR5 mAb, the first use of a CCR5 inhibitor that doesn't block the natural activity of CCR5 and the first use of a potentially long-acting CCR5 inhibitor in HFV-1 infection. Our studies are designed to establish initial proof-of-concept for PRO 140 in single- and multi-dose settings via two randomized clinical trials, and these studies will provide new insights into the effects of CCR5 inhibitor therapy on immune parameters. The first (Phase 1b) study will explore escalating single intravenous doses of PRO 140 in subjects with early-stage disease. The second (Phase 2a) trial will examine monthly infusions of PRO 140 administered for 16 weeks in combination with existing antiretrovirals. This clinical research is closely integrated with the laboratory studies of Projects 1 and 3, and collectively the collaborative Projects seek to identify critical viral and host determinants of effective CCR5-targeted therapy. Success in Project 2 would establish clinical proof-of-concept for PRO 140 as a novel, long-acting, and non-toxic treatment strategy for HIV-1 infection. More broadly, these integrated preclinical/clinical studies will provide new molecular-level insight into how to best deploy CCR5 inhibitors for maximum patient benefit.